CHARACTERIZATION OF THE ORIGINS OF ASTROCYTE RESPONSE TO INJURY USING THE DOPAMINERGIC NEUROTOXICANT, 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE
CHARACTERIZATION OF THE ORIGINS OF ASTROCYTE RESPONSE TO INJURY USING THE DOPAMINERGIC NEUROTOXICANT, 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE
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DOI：
10.1016/0006-8993(90)91526-m
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发表时间：
1990-06-25
期刊：
影响因子：
2.9
通讯作者：
REINHARD, JF
中科院分区：
文献类型：
--
作者：
OCALLAGHAN, JP;MILLER, DB;REINHARD, JF
我们使用多巴胺能神经毒物1-甲基-1,2,3,6-四氢吡啶（MPTP）作为表征星形胶质细胞损伤反应起源的工具。星形胶质细胞蛋白，胶质原纤维酸性蛋白（GFAP）的放射免疫测定用于定量星形胶质细胞对MPTP的反应。神经元定位蛋白和多巴胺测定用于评估MPTP引起的神经元损伤。单次给C57BL/6J小鼠MPTP （12.5 mg/kg, s.c）导致纹状体GFAP在48小时内增加3倍以上，随后在3周时下降到基线水平。纹状体酪氨酸羟化酶（TH）（多巴胺能神经元的标志物）的数量减少先于GFAP的升高。纹状体DARPP-32（一种在接受多巴胺能输入的神经元中富集的磷蛋白）的浓度不受MPTP的影响。保护多巴胺能神经元免受MPTP的神经毒性代谢物，1-甲基-4-苯基吡啶（MPP+），通过阻断其形成或阻止其摄取到多巴胺能神经元，完全阻断GFAP的增加。MPTP似乎没有破坏血脑屏障，因此，血源性元素可能没有介导GFAP的增加。此外，免疫印迹数据显示，脑源性白细胞介素1（一种星形细胞生长因子）在mptp诱导的胶质细胞形成中也没有发挥作用。总之，这些发现表明，来自受损多巴胺能神经元的扩散因子启动了星形胶质细胞对MPTP的反应，而GFAP的大量增加可以在没有血清源性生长因子参与的情况下诱导。由于GFAP对MPTP反应的短暂性与活性毒物的快速消除相吻合，MPP+表明，维持反应性胶质瘤，一般来说，可能需要持续存在诱导损伤的损伤。
We used the dopaminergic neurotoxicant, 1-methyl-1,2,3,6-tetrahydropyridine (MPTP), as a tool to characterize the origins of astroglial response to injury. Radioimmunoassay of the astrocyte protein, glial fibrillary acidic protein (GFAP), was used to quantify the astrocyte reaction to MPTP. Assays of neuron-localized proteins and of dopamine were used to assess neuronal damage caused by MPTP. A single administration of MPTP (12.5 mg/kg, s.c.) to the C57BL/6J mouse resulted in more than a 3-fold increase in striatal GFAP within 48 h, followed by a decline to baseline at 3 weeks. A decrease in the amount of striatal tyrosine hydroxylase (TH), a marker of dopaminergic neurons, preceded the rise in GFAP. The concentration of striatal DARPP-32, a phosphoprotein enriched in neurons receiving dopaminergic input, was not affected by MPTP. Protecting the dopaminergic neurons from the neurotoxic metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+), either by blocking its formation or by preventing its uptake into dopaminergic neurons, completely blocked the increase in GFAP. MPTP did not appear to disrupt the blood-brain barrier, therefore, blood-borne elements probably did not mediate the increase in GFAP. In addition, immunoblot data indicated that brain-derived interleukin 1, an astrocyte growth factor, also did not play a role in MPTP-induced gliosis. Together, these findings suggest that diffusible factors derived from damaged dopaminergic neurons initiate the astrocyte response to MPTP and that large increases in GFAP can be induced without the participation of serum-derived growth factors. Because the transient nature of GFAP reaction to MPTP coincides with the rapid elimination of the active toxicant, MPP+, suggests that maintenance of reactive gliosis, in general, may require the continued presence of the damage-inducing insult.